The healing of cartilage lesions with currently available cell based therapies is hampered by the inconsistent retention and growth of the transplanted cells.
Likewise, nerve regeneration following injury is inhibited by multiple signals coming from the microenvironment of the glial scar, and biomaterials with a potent capacity to stimulate neurogenesis would have a high clinical importance.
Alginates, as an example of such a biomaterial, are natural polymers that consist of two monosaccharides, β-D-mannuronic acid (M) and α-L-guluronic acid (G), arranged in homopolymeric (poly-mannuronate or poly-guluronate) or heteropolymeric block structures (FIG. 1). They can be extracted from brown seaweed and do not exert any strong immunological reaction when injected into mammalian tissues [Suzuki et al., Journal of Biomedical Materials Research. 1998; 39:317-22].
Alginate is fully biocompatible, FDA-approved and used widely in tissue engineering, regenerative medicine, cell encapsulation and drug delivery. Its properties can be tuned by varying the amount of α-L-guluronic acid (G) and (1,4)-linked β-D-mannuronic acid (M) and by functionalization with growth factors and adhesion molecules, such as a RGD-peptide (arginylglycylaspartic acid).
Alginate has been widely used, in combination with other biomaterials and/or functionalized with growth factors, as a drug delivery system and scaffold for tissue engineering. Francis et al. show that fibroblasts expressing brain-derived neurotrophic factor (Fb/BDNF) can be incorporated in alginate and guide neurite outgrowth of dorsal root ganglia (DRGs) [Francis et al., Journal of microencapsulation. 2011; 28:353-62]. Growth factors (GFs) can also bind directly to alginate, with their release being regulated by the disruption of ionic bridges between the positively charged factors and the poly-anionic alginate. NGF-grafted alginate/poly (gamma-glutamic acid) hydrogels have been used for inducing the neural differentiation of induced pluripotent stem cells [Kuo and Chang, Colloids and surfaces B, Biointerfaces. 2012; 102C:405-11]. Moreover, the sulfation of uronic acids of alginate provides specific and strong binding to heparin-binding proteins, some of which do not normally bind to pure alginate. For instance, an alginate sulfate scaffold can sustain basic fibroblast growth factor (bFGF) release to the extracellular medium [Freeman et al., Biomaterials. 2008; 29:3260-8], as well as TGF-β release, the latter inducing chondrogenic differentiation of human mesenchymal stem cells [Re'em et al, Biomaterials. 2012; 33:751-61].
Alginate sulfate has been shown to possess anticoagulant properties similar to that of heparin [Ronghua et al., Carbohydrate Polymers. 2003; 52:19-24].
It is the objective of the present invention to provide means and methods for tissue engineering and for regenerative treatment, particularly for the treatments of cartilage lesions or nerve damage.
The objective is attained by the subject-matter of the independent claims.